This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mechanisms by which replication of HCV is controlled and eventually terminated by those individuals that are able to resolve infection remain unclear, however are of paramount importance both to the production of an effective vaccine for this pathogen, and to future development of effective therapies. In experiments in transgenic mouse models and the chimpanzee, it has been demonstrated that control of hepatitis B virus replication can be controlled by secretion of the cytokine IFN-gamma by immune cells (Guidotti and Chisari. Ann Rev Immunol 2001;19: 65-89), rather than viral control requiring killing of infected cells by the immune system. Experiments using in vitro systems suggest that IFN-gamma could contribute to control of HCV replication (Frese et al Hepatology 2002;35:694[unreadable]703;Lanford et al J Virol 2003;77: 1092-1104). However this in vitro data does not necessarily reflect in vivo events. A single study has been carried out examining whether supplementation of IFN-gamma alters viral replication in chronic HCV infection (Shin et al. J Virol 2005;79: 13412-30);however it is likely that both the infecting virus has escaped from HCV-specific responses and that persisting HCV-specific immune responses are defective by this stage of infection (Bowen and Walker. Nature 2005;436: 946-52). This data is thus unlikely to reflect the role played by IFN-gamma in natural control of infection in individuals that resolve infection.